title: Levosimendan Relaxes Pulmonary Arteries and Veins in Precision-Cut Lung Slices - The Role of KATP-Channels, cAMP and cGMP.
abstract: Levosimendan is approved for left heart failure and is also used in right heart failure to reduce right ventricular afterload. Despite the fact that pulmonary arteries (PAs) and pulmonary veins (PVs) contribute to cardiac load, their responses to levosimendan are largely unknown.
  
  
  
  Levosimendan-induced vasorelaxation of PAs and PVs was studied in precision-cut lung slices from guinea pigs by videomicroscopy; baseline luminal area was defined as 100%. Intracellular cAMP- and cGMP-levels were measured by ELISA and NO end products were determined by the Griess reaction.
  
  
  
  Levosimendan relaxed control PVs (116%) and those pre-constricted with an endothelinA-receptor agonist (119%). PAs were only relaxed if pre-constricted (115%). Inhibition of KATP-channels (glibenclamide), adenyl cyclase (SQ 22536) and protein kinase G (KT 5823) largely attenuated the levosimendan-induced relaxation in control PVs, as well as in pre-constricted PAs and PVs. Inhibition of BKCa (2+)-channels (iberiotoxin) and Kv-channels (4-aminopyridine) only contributed to the relaxant effect of levosimendan in pre-constricted PAs. In both PAs and PVs, levosimendan increased intracellular cAMP- and cGMP-levels, whereas NO end products remained unchanged. Notably, basal NO-levels were higher in PVs. The KATP-channel activator levcromakalim relaxed PAs dependent on cAMP/PKA/PKG and increased cAMP-levels in PAs.
  
  
  
  Levosimendan initiates complex and divergent signaling pathways in PAs and PVs. Levosimendan relaxes PAs and PVs primarily via KATP-channels and cAMP/cGMP; in PAs, BKCa (2+)- and Kv-channels are also involved. Our findings with levcromakalim do further suggest that in PAs the activation of KATP-channels leads to the production of cAMP/PKA/PKG. In conclusion, these results suggest that levosimendan might reduce right ventricular afterload by relaxation of PAs as well as pulmonary hydrostatic pressure and pulmonary edema by relaxation of PVs.
authors.affiliation: Institute of Pharmacology and Toxicology, Medical Faculty Aachen, Rhenish Westphalian Technical University, Aachen, Germany ; Department of Anesthesiology, Medical Faculty Aachen, Rhenish Westphalian Technical University, Aachen, Germany.
authors.forename: Annette D
authors.initials: AD
authors.lastname: Rieg
authors.forename: Rolf
authors.initials: R
authors.lastname: Rossaint
authors.forename: Eva
authors.initials: E
authors.lastname: Verjans
authors.forename: Nina A
authors.initials: NA
authors.lastname: Maihöfer
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlig
authors.forename: Christian
authors.initials: C
authors.lastname: Martin
mesh_terms: D000818:Animals; D003470:Culture Media; D000242:Cyclic AMP / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology*; D005260:Female; D006168:Guinea Pigs; D006835:Hydrazones / Q000494:pharmacology*; D054086:KATP Channels / Q000502:physiology*; D008168:Lung / Q000098:blood supply*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology*; D000077464:Simendan; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D003470:Culture Media; D006835:Hydrazones; D054086:KATP Channels; D011724:Pyridazines; D000077464:Simendan; D000242:Cyclic AMP; D006152:Cyclic GMP